Cascade of caspase activation in potassium-deprived cerebellar granule neurons: targets for treatment with peptide and protein inhibitors of apoptosis

Mol Cell Neurosci. 2001 Apr;17(4):717-31. doi: 10.1006/mcne.2001.0962.

Abstract

Cerebellar granule neurons (CGN) cultured in the presence of serum and depolarizing potassium concentrations undergo apoptosis when switched to serum-free medium containing physiological potassium concentrations. Here we show that processing of the key protease, caspase-3, depends on the activation of caspase-9, but not of caspase-8. Selective peptide inhibitors of caspase-9 block processing of caspase-3 and caspase-8 and inhibit apoptosis, whereas a selective inhibitor of caspase-8 blocks neither processing of caspase-3 nor cell death. The data obtained with peptide inhibitors were confirmed by adenovirally mediated ectopic expression of the cytokine response modifier A (crmA), the baculovirus protein p35, and the X chromosome-linked inhibitor of apoptosis (XIAP). Further, caspase-8-activating death receptors do not mediate apoptosis in CGN and potassium withdrawal-induced apoptosis evolves unaltered in gld or lpr mice, which harbor mutations in the CD95/CD95 ligand system. Thus, neuronal apoptosis triggered by potassium deprivation is death receptor-independent but involves the mitochondrial pathway of caspase activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors
  • Caspases / metabolism*
  • Cell Survival / physiology
  • Cells, Cultured
  • Cerebellum / cytology*
  • Coumarins / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Enzyme Precursors / antagonists & inhibitors
  • Enzyme Precursors / metabolism
  • Gene Expression Regulation, Viral
  • Inhibitor of Apoptosis Proteins
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Neurons / cytology*
  • Neurons / enzymology*
  • Oligopeptides / pharmacology
  • Potassium / pharmacology*
  • Proteins / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Serpins / genetics
  • Specific Pathogen-Free Organisms
  • Transgenes / physiology
  • Viral Proteins / genetics
  • X-Linked Inhibitor of Apoptosis Protein

Substances

  • Caspase Inhibitors
  • Coumarins
  • Enzyme Inhibitors
  • Enzyme Precursors
  • Inhibitor of Apoptosis Proteins
  • Oligopeptides
  • Proteins
  • Serpins
  • Viral Proteins
  • X-Linked Inhibitor of Apoptosis Protein
  • acetyl-aspartyl-glutamyl-valyl-aspartyl-amino-4-methylcoumarin
  • inhibitor of apoptosis, Nucleopolyhedrovirus
  • interleukin-1beta-converting enzyme inhibitor
  • Casp3 protein, mouse
  • Casp3 protein, rat
  • Casp8 protein, mouse
  • Casp8 protein, rat
  • Casp9 protein, mouse
  • Casp9 protein, rat
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases
  • Potassium